The proposed study will develop and employ theoretical methods to investigate protein-protein and protein-DNA association phenomena in aqueous media, dealing with both equilibrium and dynamical aspects. Attention will be especially directed toward the crucial solvent and electrolyte effects which mediate macromolecular interactions in physiological aqueous solutions. Specific projects include: (i) A study of protein-protein electrostatic interactions, with the development and application of several strategies which will allow the rapid computation of accurate protein-protein (and protein-nucleic acid) electrostatic interaction potentials to benefit Brownian dynamics simulations and other automated docking procedures requiring rapid calculation of energies from look-up tables; (ii) The continued refinement and testing of the Brownian dynamics simulation method by the inclusion and evaluation of limited surface atom flexibility and empirical methods for rapid computation of electrostatic forces. (Application will be made to association and electron transfer reactions in the cytochromes and mutants to further our understanding of the role of a variety of influences on cytochrome electron transfer); iii) Simulation of nonspecific binding of genome regulatory proteins to DNA by an adaptation of existing Brownian dynamics methodology to study nonspecific protein-DNA associations. (Dynamical aspects of nonspecific binding of cro repressor protein and the E. coli catabolite gene activator protein to B-DNA will be studied); and iv) Development of software for systematic searching of optimum docking conformations of protein-protein and protein-DNA complexes, allowing an automated force-guided exhaustive search of docked conformers which would avoid trapping in local energy minima with user-intervention.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM034248-05
Application #
3284894
Study Section
Special Emphasis Panel (SSS (A))
Project Start
1985-09-25
Project End
1995-03-31
Budget Start
1991-04-01
Budget End
1992-03-31
Support Year
5
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Tennessee Technological University
Department
Type
Schools of Arts and Sciences
DUNS #
City
Cookeville
State
TN
Country
United States
Zip Code
38501
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Northrup, S H; Thomasson, K A; Miller, C M et al. (1993) Effects of charged amino acid mutations on the bimolecular kinetics of reduction of yeast iso-1-ferricytochrome c by bovine ferrocytochrome b5. Biochemistry 32:6613-23
Northrup, S H; Erickson, H P (1992) Kinetics of protein-protein association explained by Brownian dynamics computer simulation. Proc Natl Acad Sci U S A 89:3338-42
Eltis, L D; Herbert, R G; Barker, P D et al. (1991) Reduction of horse heart ferricytochrome c by bovine liver ferrocytochrome b5. Experimental and theoretical analysis. Biochemistry 30:3663-74
Northrup, S H; Wensel, T G; Meares, C F et al. (1990) Electrostatic field around cytochrome c: theory and energy transfer experiment. Proc Natl Acad Sci U S A 87:9503-7
Northrup, S H; Boles, J O; Reynolds, J C (1988) Brownian dynamics of cytochrome c and cytochrome c peroxidase association. Science 241:67-70
Northrup, S H; Luton, J A; Boles, J O et al. (1988) Brownian dynamics simulation of protein association. J Comput Aided Mol Des 1:291-311